Maternal cognitive function during pregnancy in relation to hypo- and hyperthyroxinemia.

OBJECTIVE: To assess a possible relationship between maternal cognitive dysfunction during pregnancy and hypothyroxinemia, adjusted for major confounders. BACKGROUND: Thyroid dysfunction in general is associated with cognitive dysfunction. Cognitive dysfunction is common during pregnancy. DESIGN: Prospective follow-up study from 12 to 32 weeks of pregnancy. PARTICIPANTS: 2082 healthy pregnant women. MEASUREMENTS: Cognitive function, depression and sleeping problems were assessed by self-report questionnaires at 12, 22 and 32 weeks of gestation, higher scores reflecting more symptoms. FT4, TSH and TPO-Ab were assessed at 12 weeks of gestation. DEFINITIONS: healthy (euthyroxinemia) control group: FT4 within 10-90th percentiles, without elevated TPO-Ab titres and TSH within first trimester-specific reference range (0.23-4.0 mU/L). Hypothyroxinemia: FT4 <2.5th percentile with TSH within first trimester-specific reference range. Poor cognitive function: a score >1 SD > mean on the cognitive function scale. RESULTS: A total of 54 women showed hypothyroxinemia and 1476 women had euthyroxinemia. At 12 weeks, multiple logistic regression showed that poor cognitive function was independently related to hypothyroxinemia: OR: 2.9 (95% CI: 1.6-5.4), adjusted for depression (OR: 3.1; 95% CI: 2.7-4.6) and sleeping problems (OR: 2.8, 95% CI: 1.9-3.9). TPO-Ab + women with hypothyroxinemia had the highest levels of cognitive dysfunction. Other cut-offs of hypothyroxinemia (<5th or <10th percentile with normal TSH) showed similar results. GLM-ANOVA showed that throughout pregnancy women with hypothyroxinemia at 12 weeks had significantly higher cognitive dysfunction scores compared with the healthy controls: F = 12.1, P = .001. CONCLUSIONS: Women with hypothyroxinemia during early gestation are at risk for poor cognitive function throughout gestation, adjusted for depression and sleeping problems.

Thyroid hormone receptor ß mediates thyroid hormone effects on bone remodeling and bone mass.

Excess thyroid hormone (TH) in adults causes osteoporosis and increases fracture risk. However, the mechanisms by which TH affects bone turnover are not elucidated. In particular, the roles of thyroid hormone receptor (TR) isotypes in the mediation of TH effects on osteoblast-mediated bone formation and osteoclast-mediated bone resorption are not established. In this study we have induced experimental hypothyroidism or hyperthyroidism in adult wild-type, TRα- or TRß-deficient mice and analyzed the effects of TH status on the structure and remodeling parameters of trabecular bone. In wild-type mice, excess TH decreased bone volume and mineralization. High TH concentrations were associated with a high bone-resorption activity, assessed by increased osteoclast surfaces and elevated concentrations of serum bone-resorption markers. Serum markers of bone formation also were higher in TH-treated mice. TRα deficiency did not prevent TH action on bone volume, bone mineralization, bone formation, or bone resorption. In contrast, TRß deficiency blocked all the early effects of excess TH observed in wild-type mice. However, prolonged exposure to low or high TH concentrations of TRß-deficient mice induced mild modifications of bone structure and remodeling parameters. Together our data suggest that TRß receptors mediate the acute effects produced by transient changes of TH concentrations on bone remodeling, whereas TRα receptors mediate long-term effects of chronic alterations of TH metabolism. These data shed new light on the respective roles of TRs in the control of bone metabolism by TH.

The coexistence of a novel inactivating mutant thyrotropin receptor allele with two thyroid peroxidase mutations: a genotype-phenotype correlation.

CONTEXT: TSH receptor (TSHR) and thyroid peroxidase (TPO) gene mutations occur independently. This is the first report of their coexistence in the same individuals. OBJECTIVES: The objective of the study was to evaluate the genotype-phenotype correlations when mutations in both genes are present alone or together in the same individual. PATIENTS AND METHODS: Thirty subjects from an extended Arab kindred underwent clinical investigation and molecular studies of the mutant TSHRs. RESULTS: A novel mutant TSHR was identified, involving four nucleotides at three sites on the same allele, c.267G>T (L89L), c.269/270AG>CT (Q90P), and c.790C>T (P264S). In addition, two known TPO gene mutations, G493S and R540X, were identified. Thirteen heterozygotes for the mutant TSHR allele had mild hyperthyrotropinemia. In nine of theses, the coexistence of a TPO mutation in one allele did not magnify the hyperthyrotropinemia. Homozygotes for the mutant TSHR and a compound heterozygote for the TPO mutations presented frank hypothyroidism. In vitro studies showed increasing loss of function for Q90P less than P264S less than Q90P/P264S TSHR mutants, the latter being that expressed in the subjects under investigation. The two interchangeably used WT TSHR vectors, L87 and V87, although functionally identical, differed in structure and function in the presence of the Q90P mutation. CONCLUSIONS: TSHR and TPO gene mutations were identified alone and together in individuals of a consanguineous kindred. Homozygotes for the TSHR and a compound heterozygote for the TPO mutations were hypothyroid. The mild hyperthyrotropinemia of heterozygotes for the mutant TSHR allele was not aggravated by the coexistence of a TPO defect in one allele.

T4 plus T3 treatment in children with hypothyroidism and inappropriately elevated thyroid-stimulating hormone despite euthyroidism on T4 treatment.

AIMS: To evaluate the effect of addition of T3 to L-T4 treatment in children with congenital hypothyroidism (CH) who have inappropriately elevated thyroid-stimulating hormone (TSH) levels despite high normal serum T4 levels on L-T4 treatment. METHODS: Ten children (age 7.1 +/- 2 years) with CH whose TSH levels were persistently high despite euthyroidism and can only be normalized with hyperthyroidism were included. L-T4 treatment was switched to T3+L-T4 combination (Bitiron(R) tablet 50 mug L-T4 + 12.5 mug triiodothyronine). The patients received 50% of their usual L-T4 dose as L-T4 and the remaining half as T3 in a 4:1 ratio. The dose of T3+L-T4 was titrated to achieve normal TSH levels. Thyroid hormones and biochemical markers were followed for 1 year. RESULTS: Euthyrotropinemia was achieved at the 7th month (mean) of combination (T3+L-T4) treatment. Serum T4 and fT4 were lower and T3 was higher during combination compared to L-T4 treatment. LDL-cholesterol decreased and ALP increased in the euthyrotropinemic state. Vital signs were similar at hyperthyrotropinemia and euthyrotropinemia. CONCLUSION: T3+L-T4 treatment provides euthyrotropinemia without causing hyperthyroidism in children with CH and inappropriate hyperthyrotropinemia. Our data strongly suggest that decreased negative feedback due to lower T3 levels at the pituitary level is the main reason for persistent hyperthyrotropinemia.

Effects of experimental increases and decreases in thyroxine levels on the extent of cataleptic freezing reactions in rats.

Numerous clinical observations have provided evidence for a tight connection between impairments in the functions of the hypothalamo-hypophyseal-thyroid system and nervous and mental disorders. The aim of the present work was to compare the effects of experimental decreases and increases in blood thyroxine levels on the extents of two types of pathological freezing reaction in male Wistar rats--spontaneous catalepsy and catalepsy evoked by pinches at the nape of the neck (pinch-induced catalepsy). Chronic administration of the thyroxine synthesis inhibitor propylthiouracil (5 mg/kg/day for 28 days) significantly decreased the blood hormone level and sharply increased the proportion of animals showing spontaneous catalepsy and the immobility time, but had no effect on the extent of pinch-induced catalepsy. At the same time, chronic administration of thyroxine (0.1 mg/kg/day for 28 days), which produced significant increases in blood hormone levels, had no effect on the extent of spontaneous catalepsy but significantly increased the proportion of animals showing pinch-induced catalepsy and the duration of this type of catalepsy. It is concluded that both insufficiency and excess of thyroid hormones have cataleptogenic actions, but enhance different types of catalepsy.

[The specific features of thyrotoxicosis and euthyroid hyperthyroxinemia developed due to the use of cordarone]. / Osobennosti tireotoksikoza i eutireoidnoi gipertiroksinemii, razvivaiushchikhsia na fone priema kordarona.

Thyrotoxicosis (TT) is one of the thyroid (T) dysfunctions occurring with the use of cordarone. The clinical features of TT were studied in cordarone-treated patients living in Moscow and its regions (mild and moderate iodine deficiency regions). The patients were examined by using currently available procedures for measuring thyroid-stimulating hormone, free thyroxine, free triiodothyronine, antibodies to TH, TPO, interleukin-6 (IL-6), and C-reactive protein (CRP), and by employing T ultrasound study, Holter ECG monitoring. TT was ascertained to develop in the presence of both the pathologically altered (16/23, 69%) and intact T (7/23, 31%). Examining the course of cardiac arrhythmias (CA) in developed TT has established that this condition gives rise to their recurrence. As compared with the control group, the patients with TT were not found to have higher levels of IL-6 and CRP (p > 0.05; Mann-Whitney test). Therapy with thyrostatic agents alone or in combination with glucocorticosteroids normalizes the levels of thyroid hormonesfollowing, on the average, 2-3 months. Euthyroid hyperthyxinemia (EHT) is frequently recorded with the use of cordarone. Examination of 20 patients with EHT has revealed organic pathology in 13 (65%) patients and its absence in 7 (35%). Recurrences of prior CA have not been found in EHT (p < 0.05; McNemar test). The confidence interval for the difference of relative frequencies of signs did not include 0). Thus, TT is a condition that leads to the fact that cordarone loses its antiarrhythmic effects and TT requires compulsory treatment. If required, therapy should be performed during the continued administration of the drug. EHT is not thyrotoxicosis, which is to be followed up.

Thyroid dysfunction in children with Down's syndrome.

UNLABELLED: Thyroid function tests were carried out on 320 children with Down's syndrome aged between 5 d and 10 y. Thyroid function was normal in 230 patients (71.9%) and abnormal in 90 (28.1%). Six patients (1.8%) had primary congenital hypothyroidism, one patient had acquired hypothyroidism and two had transient hyperthyrotropinaemia of the newborn. Sixteen of the remaining 81 patients (25.3%) had compensated hypothyroidism with increased thyroid-stimulating hormone (TSH) levels (11-20 mU l(-1)). Their T4 levels were found to be either normal or close to the lower limit of normal. These cases were started on thyroxine therapy. Sixty-five of the 81 patients had a mild compensated hypothyroidism with mild TSH elevation (6-10 mU l(-1)). None of the patients had hyperthyroidism. The antithyroid antibodies were positive in the acquired hypothyroidism case. CONCLUSION: The prevalence of congenital hypothyroidism was 1.8% in children with Down's syndrome while 25.3% of them had compensated hypothyroidism. It is suggested that Down's syndrome patients with normal thyroid functions and those with compensated hypothyroidism should be followed annually and every 3 mo, respectively. Besides congenital hypothyroidism cases, those with TSH levels between 11 and 20 mU l(-1) may benefit from treatment with low-dose thyroxine.

Thyroxine affects physiological and morphological development of the ear.

The onset and development of distortion product otoacoustic emissions (DPE) representing cochlear amplifier activity were studied in neonatal hyperthyroid (n = 10) and control (n = 10) rat pups. These were compared to the onset and development of auditory nerve-brainstem evoked responses (ABR) representing overall cochlear function, and to morphological development of the ear. DPEs were recorded at an earlier postnatal age to high (8 kHz) frequencies and progressed to lower (3 kHz) frequencies with age. ABRs to high-intensity clicks were recorded at least 2 days before DPEs, although DPE onset at 8 kHz preceded adult-like ABR thresholds. Both ABR and DPEs appeared earlier in the hyperthyroid rats. Histological evidence showed earlier morphological development of the ear in these animals. ABR thresholds and DPE amplitudes matured at a slower rate in the experimental group despite their earlier onset. There was no difference in ABR and DPE thresholds between adult hyperthyroid and control rats. However, in the experimental group, DPEs had smaller amplitudes to high (70 dB SPL) and to low (50 dB SPL) stimulus intensities at low frequencies. Hence, despite thyroxine-injected rat pups having earlier onset of auditory structure and function (lower ABR thresholds and earlier functioning active cochlear amplifier), it appeared that neonatal hyperthyroidism affected the later state of the cochlea, such that DPEs, especially to low-frequency stimuli, were depressed during and after maturation.

Resistance to thyroid hormone--an uncommon cause of thyroxine excess and inappropriate TSH secretion.

Resistance to thyroid hormone (RTH) is an uncommon inherited cause of hyperthyroxinemia with inappropriate TSH secretion. The syndromes are characterized by reduced target tissue responsiveness to circulating free thyroid hormones. The differential diagnosis to other diseases with similar laboratory results (high T4 with normal TSH) like familial dysalbuminemia or antibodies against iodothyronines or TSH is now possible with the appropriate use of new assays for free thyroid hormones. In the presence of thyrotoxic symptoms it may be difficult to differentiate the syndrome from a TSH-secreting pituitary tumour. Familial occurrence and a normal TSH-response to TRH that can not be suppressed by T3 are characteristic features of RTH, that may be helpful in that respect. The majority of RTH cases are dominantly inherited and have highly variable clinical signs and symptoms. There are, however, mainly two forms of the syndrome that have been shown to overlap clinically and biochemically, namely a generalised resistance (GRTH) and a more "selective" pituitary resistance to thyroid hormones (PRTH). The absence of thyrotoxic symptoms rather suggests GRTH, whereas thyrotoxic signs seem to be characteristic for PRTH. Following the cloning of thyroid hormone receptors, familial GRTH was shown to be tightly linked to the TR-(Thyroid hormone receptor)-beta gene locus. Molecular genetic studies have shown that even within a single kindred the same receptor mutation was associated with both, GRTH or PRTH, and therefore suggest that these two forms represent part of a variable clinical spectrum of a single genetic disorder.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of thyroxine excess on peripheral organs.

Aim of this paper is to review the effects of T4 excess due to exogenous thyroid hormone administration on target organs, with particular regard to heart, bone, liver and pituitary. Therapy with TSH-suppressive doses of T4 has been shown in a cross sectional echocardiographic study to increase left ventricular contractility and to induce mild myocardial hypertrophy. Whether the latter represents a risk for the patients remains a matter of debate. Clinically it does not seem to be important. The long-term evaluation of T4-therapy has provided controversial results. Some have reported that T4-treated patients under the age of 65 have an increased risk of ischemic heart disease, whereas others were unable to find any change in morbidity, mortality and quality of life, including cardiovascular events. Thyroid hormones enhance both osteoblastic and osteoclastic activities in cortical and trabecular bone. Overt hyperthyroidism is well known to represent a risk factor for osteoporosis. Studies in the late eighties have suggested a reduced bone density in T4-treated patients, with a particular risk for cortical bone in postmenopausal women. More recent studies have failed to show any substantial T4-related change in bone mass. Taken together the evidence of the literature suggests that TSH-suppressive therapy with T4 is, if well controlled, probably not associated with significant loss of bone mass at least in premenopausal women. A mild elevation of the activity of hepatic enzymes (glutathione-S-transferase, gamma glutamyltransferase, alanine amino-transferase, angiotensin-converting enzyme) has been observed in patients under T4 treatment in TSH-suppressive doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroxine excess and pregnancy.

Pregnancy is characterised by a physiological increase in bound thyroxine but normal values of free hormone. Human chorionic gonadotrophin (hCG may stimulate the thyroid to produce hyperemesis gravidarum (with mild to moderate hyperthyroidism) or result in high thyroid hormone levels associated with gestational trophoblastic disease. Hyperthyroidism occurring during pregnancy is usually due to Graves' disease and must be treated to prevent congenital anomalies, low birth weight and premature labour. Thionamide drugs should be used with a preference for propylthiouracil (PTU) and continued in low doses up to labour. Breast feeding is possible in patients on low dose PTU. In the management of hypothyroidism during pregnancy thyroxine dose may require to be increased but excess dosage should be avoided because of its unwanted effects on foetal cerebral maturation. Neonatal hyperthyroidism due to transplacental passage of thyroid stimulating antibodies (TsAb) should be checked for in pregnant patients with autoimmune thyroid disease. As antithyroid drugs cross the placenta they may be used as therapy in this condition. Prevention of neonatal goitre is vital. Postpartum development of hyperthyroidism may be due to an exacerbation of pre-existing Graves' disease, development of new Graves' hyperthyroidism or postpartum thyroiditis with transient hyperthyroidism. Differentiation by measurement of TsAb and thyroidal iodine uptake is important because of therapeutic considerations.

The effects of danazol on a patient with familial dysalbuminemic hyperthyroxinemia.

Familial dysalbuminemic hyperthyroxinemia, a syndrome involving an abnormal affinity of albumin for thyroxine, results in elevated total thyroxine and free thyroxine index levels but normal triiodothyronine resin uptake and thyroid-stimulating hormone levels. Danazol is a synthetic androgen that increases triiodothyronine resin uptake and decreases total thyroxine, secondary to a decrease in thyroid-binding globulin levels. A 35-year-old woman with familial dysalbuminemic hyperthyroxinemia who was given danazol, in whom nervousness, insomnia, and weight gain developed, is described. Thyroid tests performed after initiation of danazol therapy revealed an increase in triiodothyronine resin uptake, with persistently elevated total thyroxine and free thyroxine index levels, and normal thyroid-stimulating hormone levels. Once the danazol was withdrawn, the symptoms resolved, the triiodothyronine resin uptake returned to normal, and the thyroid-stimulating hormone remained normal. The effects of danazol on a patient with familial dysalbuminemic hyperthyroxinemia correlate well with the effects on normals, and the ultrasensitive thyroid-stimulating hormone was the most useful test in separating hyperthyroxinemia from hyperthyroidism.

Familial generalised resistance to thyroxine: case study.

We describe the clinical features of members of a family with an atypical form of thyroid hormone resistance syndrome, affecting thyroxine predominantly. Relevant diagnostic clinical and biochemical investigations are outlined and discussed.

Euthyroid hyperthyroxinemia and inappropriate secretion of thyrotropin. Recognition and diagnosis.

Various disease states associated with euthyroid hyperthyroxinemia and inappropriate thyrotropin secretion are becoming increasingly recognized. These diagnoses were established in six (11%) of 57 patients referred for evaluation of elevated free thyroxine index over an 11-month period. Failure to separate these entities from primary thyrotoxicosis may result in unnecessary thyroid ablative therapy and subsequent clinical confusion. Several illustrative patient summaries are presented to outline an approach to this clinical challenge.

Familial partial peripheral and pituitary resistance to thyroid hormone: a frequently missed diagnosis?

The diagnosis of partial peripheral and pituitary resistance to thyroid hormone was ultimately made in two boys, 7 and 9 years of age, and a 10-year-old girl who had goiters and hyperthyroxinemia. The boys were treated with propythiouracil and/or thyroidectomy or iodine 131 for suspected thyrotoxicosis but had poorly suppressible serum thyroid-stimulating hormone (TSH) post treatment in spite of the usual L-thyroxine replacement. The girl had increasing goiter size while receiving propylthiouracil, 100 mg every eight hours. These findings led to reevaluation of thyroid hormone dynamics in these children and their families. Twelve additional family members, 3 to 38 years of age, compatible with an autosomal dominant inheritance, were also found to have peripheral and pituitary resistance to thyroid hormone. All affected individuals had elevated serum thyroxine and triiodothyronine levels, normal to slightly elevated triiodothyronine resin uptakes, and a nonsuppressed serum TSH. The five individuals who were given thyrotropin-releasing hormone showed exaggerated TSH responses, which normalized on L-thyroxine therapy. Misdiagnosis in six of 15 family members led to significant morbidity (hypothyroidism, delayed growth, and therapy risk). A nonsuppressed serum TSH in a patient with suspected thyrotoxicosis should lead to suspicion of this disorder. Appropriate management for this condition includes L-thyroxine therapy to decrease goiter size and normalize TSH responses to thyrotropin-releasing hormone.

Thyroid function tests in patients with familial dysalbuminaemic hyperthyroxinaemia (FDH).

Two patients with familial dysalbuminaemic hyperthyroxinaemia (FDH) are described in whom the albumin variant resulted in raised total T4 levels, and artefactually raised free T4 using a 'single-step' technique employing an analogue of T4 as tracer. The first patient was clinically euthyroid and presented with relapse of schizophrenia and abnormal thyroid function tests (total T4 336 nmol/L, total T3 4.2 nmol/L, TSH 1.8 mU/L, free T4 73 pmol/L). These results led to diagnostic confusion and the patient was treated with a short course of anti-thyroid drugs. The second patient had signs and symptoms of thyrotoxicosis at her first visit but was clinically euthyroid 5 months later when she was 10 weeks pregnant. Thyroid function tests were total T4 259 nmol/L, total T3 3.6 nmol/L, TSH 3.8 mU/L, free T4 46 pmol/L. Further studies showed both patients to be biochemically euthyroid. A variant albumin was confirmed in both patients by a screening test for FDH and by reverse-flow electrophoresis. Family studies on 10 relatives of the first patient identified eight with FDH. A simple screening procedure for the indentification of FDH is described and the use of laboratory tests in suspected cases is discussed.